BACKGROUND. Long-term thyroid hormone (TH) therapy aiming at the suppression of serum thyrotropin (TSH) has been traditionally used in the management of well differentiated thyroid cancer (ThyrCa). However, formal validation of the effects of thyroid hormone suppression therapy (THST) through randomized controlled trials is lacking. Additionally, the role--if any--of TSH effect at low ambient concentrations upon human thyroid tumorigenesis remains unclear. AIM: Evaluation of the effect of THST on the clinical outcomes of papillary and/or follicular ThyrCa. METHODS. By using a quantitative research synthesis approach in a cumulative ThyrCa cohort, we evaluated the effect of THST on the likelihood of major adverse clinical events (disease progression/recurrence and death). A total of 28 clinical trials published during the period 1934-2001 were identified; only 10 were amenable to meta-analysis. Causality was assessed by Hill criteria. RESULTS: Out of 4, 174 patients with ThyrCa, 2, 880 (69%) were reported ...

https://www.tandfonline.com/doi/pdf/10.1080/078538902321117760

Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer.

The TSH receptor (TSH-R) belongs to the superfamily of Gprotein-coupled receptors (GPCRs) (Nagayama & Rapoport, 1992; Vassart & Dumont, 1992), in a subfamily whose prototypic members are rhodopsin and adrenergic receptors (Helmreich & Hofmann, 1996). A common characteristic of GPCRs is the presence of seven transmembrane segments, subdividing the molecules into an extracellular domain (aminoterminal segments plus three extracellular loops), a transmembrane barrel (seven a helices) and an intracytoplasmic domain (three intracytoplasmic loops plus the carboxylterminal segment). Together with the other glycoprotein hormone receptors (LH/CG-R and FSH-R), the TSH-R is characterized by a particularly long aminoterminal segment (398 residues), which is responsible for high affinity binding of TSH (Parmentier et al., 1989). The intracytoplasmic domain of GPCRs contains the site(s) of interactions with G proteins, the transducers between activated receptors and the various effectors (O'Dowd et al., 1988). In human thyroid cells TSH-R interacts functionally with the Gs and Gq proteins (Fig. 1): the TSH-R is preferentially coupled to Gs leading to a stimulation of the cyclic AMP (cAMP) cascade, but at higher thyrotropin concentrations the TSH-R is also coupled to Gq, leading to the activation of the phospholipase C cascade and thus stimulating the production of diacylglycerol and inositolphosphate (IP3) (Laurent et al., 1987). As activation of phospholipase C pathway requires concentration of TSH five to 10 times higher than those needed for activation of the cAMP pathway, it is generally accepted that the main effect of TSH on the thyroid gland is to control cAMP concentrations. The cAMP pathway has been shown to positively control the function (thyroid hormones secretion) and growth of thyrocytes whereas the phospholipase C pathway is principally involved in control of iodination and thyroid hormone synthesis (Dumont et al., 1992)(Fig. 1). Because the cAMP cascade has a central role in thyroid cell function and proliferation, it is expected that interruption or inappropriate stimulation of this cascade could lead to various thyroid diseases.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2265.2001.01365.x-i2

Somatic and germline mutations of the TSH receptor and thyroid diseases.

Recent Advances in Thyroid Cancer

Objective: The cyclic AMP (cAMP) cascade is the main regulatory pathway in thyrocytes. Whilst activating mutations in the TSH receptor or in the Gs a-subunit, which increase cAMP levels, have been shown to be responsible for 80% of the autonomous adenomas, no such mutations have been observed in the other types of thyroid tumors, suggesting that other mechanisms exist. The discovery of Epac (‘exchange nucleotide protein directly activated by cAMP’), a novel cAMP-binding protein, which is strongly expressed in the thyroid, raised the possibility of a role for this protein in the generation of the unexplained cold thyroid follicular adenomas. Thus, we investigated whether activating mutations in either Epac or Rap (the downstream target of Epac) could be responsible for the generation of these thyroid nodules. Design: Epac and Rap1 (Rap1A and Rap1B) cDNAs were sequenced in 10 patients. The sequencing of the cDNAs was realized on both strands in the cold nodule and the juxtanodular tissue of each patient. Results: No mutations in either Epac or Rap1 cDNAs were found. For five patients, a polymorphism in Epac at codon 332 (Gly‐Ser) was observed. Conclusions: In this report, we show that the cAMP‐Epac‐Rap1 signaling pathway in the thyroid gland does not play a major role in the generation of cold thyroid follicular adenomas, since no mutations in either Epac or Rap1 could be observed in the 10 nodules studied.

/pdf/mutation-analysis-of-the-epac-rap1-signaling-pathway-in-cold-2l86hbso8b.pdf

Mutation analysis of the Epac--Rap1 signaling pathway in cold thyroid follicular adenomas.

Clinical Endocrinology goes electronic

Somatic mutations of the TSH receptor (TSHR) gene have been identified as the major cause of toxic thyroid adenoma. Recently, point mutations of the same gene have also been described in some differentiated thyroid carcinomas. The aim of the present study was to investigate the presence TSHR gene mutations in a series of thyroid specimens obtained from 22 consecutive patients with differentiated thyroid carcinomas (8 follicular and 14 papillary). Genomic DNA was extracted from fresh-frozen or paraffin-embedded tumor and normal surrounding parenchyma. Two fragments corresponding to the entire exon 10 and one fragment corresponding to exon 9 were amplified by PCR using biotinylated primers. PCR products were purified on streptavidin-coated magnetic beads and subjected to direct sequencing with Sequenase and 35(3)-labeled d-ATP-alphaS. Adenyl-cyclase activity in membrane preparations of 10 papillary carcinomas was also determined. No TSHR mutations were detected in these tumors. A polymorphism that encoded a single amino acid change Asp727Glu was identified in two follicular thyroid carcinomas. Adenyl-cyclase activity was normal in the ten papillary thyroid carcinomas we analyzed. In conclusion, our results suggest that clonal somatic mutations of the TSHR gene do not play a role in the pathogenesis of differentiated thyroid carcinoma.

Genetic analysis of the TSH receptor gene in differentiated human thyroid carcinomas

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Genetic analysis of the TSH receptor gene in differentiated human thyroid carcinomas